Double-Layer Tablet And Painkiller Tablet With Same Structurere

ABSTRACT

The invention discloses a double-layer tablet, wherein one layer has hole in which the ingredients of the other layer are filled; the number of said hole is 1-3, the diameters of the holes are 1-10 mm. Each layer of the double-layer tablet includes the active ingredients and the adjuvant materials and can be the rapid-release layer or sustained-release layer respectively. The preparation method: Preparing respectively a component I and a component II, both of them containing the active ingredients and the pharmaceutical excipients, and preparing the tablet having holes from component I; Forming the double-layer tablet composed of the component I layer and the component II layer after pressing said tablet having holes with the component II together; and filling the component II into the holes during compressing. It is proved by tests that the double-layer table in the invention is featured with high physical stability, hard breaking during transportation and storage, approximately constant release of medicine and usefulness of keeping stable plasma concentration of the medicine in the patient; thus, the effectiveness and safety of the medicine taken by the patient are improved greatly.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 15/107,892, now allowed, which is a U.S. National Phase ofInternational Patent Application No. PCT/CN2014/094367, filed Dec. 19,2014, which claims benefit of priority to Chinese Patent Application No.201310717968.1, filed Dec. 23, 2013, Chinese Patent Application No.201310716482.6, filed Dec. 23, 2013, and Chinese Patent Application No.201310718529.2, filed Dec. 23, 2013, the disclosures of whichapplications are incorporated by reference herein in their entiretiesfor all purposes.

TECHNICAL FIELD

The invention refers to the field of medicinal preparation, specificallya novel double-layer tablet and a preparation method thereof.

BACKGROUND TECHNOLOGY

A double-layer tablet is a double-phase medicine-release system having adouble-layer structure, which not only can achieve the idealpharmacokinetic behavior by combining two medicines together orcombining identical medicine in different release modes together, butimprove the stability of the medicines having incompatibility and givethe special functions to the tablet.

In preparation of the double-layer tablet, to ensure the medicine ofdouble-layer tablet has the stable structure during the shelf life isthe most demanding and practical technology in pharmaceuticals industry.

The double-layer tablet in the prior art includes two layers of tabletswhich are adhered to each other; and the preparation method thereof isto press the two layers of tablets one by one usually, for example, mixthe medicinal active ingredients and the pharmaceutical excipients ofone layer of the double-layer tablet and press the mixture into onelayer of tablet; then prepare the double-layer tablet after pressingthis tablet with the medicinal active ingredients and the pharmaceuticalexcipients of the other layer of tablet together.

The double-layer tablet of the prior art is featured with poor physicalstability, easy breaking and separation of the two layers; and thepreparation may be cracked, etc. during transportation and storage as aresult of difference of dilatation coefficients among the differentpharmaceutical excipients because different pharmaceutical excipientsare applied to the two layers of tablets usually.

Therefore, it is necessary to improve the physical stability of thedouble-layer tablet and ensure integrity of the preparation duringtransportation and storage.

CONTENTS OF THE INVENTION

The invention is to provide a double-layer tablet, which featured withhigh physical stability, not easy to broken during transportation andstorage, approximately constant release of medicine and capability ofimproving effectiveness and safety of the patient taking the medicine.

The invention achieves the purpose of the above-mentioned invention bydesigning the double-layer tablet having a new structure, wherein thetechnical solution is as follows:

The double-layer tablet refers to a double-layer medicine-release mode,which is formed by combining two layers of tablets together, wherein onelayer of tablet has hole. Moreover, said hole has the ingredients of theother layer of tablet when the preparation is prepared.

Each layer of said double-layer tablet includes the active ingredientsand pharmaceutical excipients, wherein the active ingredients in eachlayer can be one or two or more than two active ingredients.

The active ingredients in two layers of the double-layer tablet can bethe same or different from each other.

Each layer of the double-layer tablet can be the quick release layer orthe sustained-release layer, respectively.

The number of said holes is 1-3, preferably 1.

The diameters of said holes are 1-10 mm, preferably 2-6 mm.

Said double-layer tablet can be coated, etc. by using the conventionalmethod in this field in accordance with the actual need.

A method of preparing said double-layer tablet includes the steps of:

-   -   1) Preparing respectively a component I and a component II, both        of them containing the active ingredients and the pharmaceutical        excipients, and said component I and the component II are        granules or powder;    -   2) Implementing the first tabletting: preparing the tablet        having hole from component I (also called tablet I below);    -   3) Implementing the second tabletting: forming the double-layer        tablet composed of the component I layer and the component II        layer after pressing said tablet having holes with the component        II together; and filling the component II into the holes during        compressing.    -   Said hole can be formed by using a compressing mould having        holes, or punching the tablets after compressing

Moreover, in one embodiment of the invention, the tablet I with hole isformed from the component I by using an annular punch.

As for the advantages of the invention, the component I layer of thedouble-layer tablet has holes; the double-layer tablet acquired is veryfirm and cannot be separated during transportation and storage becausethe component II is filled in the holes of the tablet I. See FIG. 1-3for structure.

The preparation method of the double-layer tablet in the invention isapplicable for preparation of all kinds of double-layer tablet. Further,the technicians in this field can select all kinds of conventionalpharmaceutical excipients in accordance with actual need.

The pharmaceutical excipients is one or more selected fromsustained-release material, filler, disintegrating agent, lubricant,binder and glidant. The sustained-release material is one or morepreferably selected from hydroxypropyl methylcellulose, ethyl celluloseand hydroxy propyl cellulose; the filler is one or more preferablyselected from lactose, pregelatinized starch and microcrystallinecellulose; the disintegrating agent is one or more preferably selectedfrom sodium carboxymethyl cellulose, sodium carboxymethyl starch andpolyvinylpolypyrrolidone; the lubricant is one or more preferablyselected from stearic acid, magnesium stearate and talcum powder; thebinder is one or more preferably selected from polyvidone, hydroxypropyl cellulose and hydroxylpropyl methylcellulose; and the glidant issuperfine silica powder preferably.

The component I in the invention preferably includes followingingredients with percentages by weight:

Medicine 1-60% Sustained-release material 0-25% Disintegrating agent 0-6% Binder  0~5% Filler 5-60% Lubricant 0.1-0.5%  Glidant 0.1-0.5% 

The granules II in the invention preferably include followingingredients with percentages by weight:

Medicine 1~90% Sustained-release material 0~40% Disintegrating agent 0~6% Binder  0~5% Filler 5~90% Lubricant 0.1~0.5%  Glidant 0.1~0.5% 

The double-layer table of the invention also includes the coatingpreferably, wherein the coating comprises following components withpercentage:

Hydroxypropylmethyl-cellose E5 40-60% Polysorbate 80 20-35% Talcumpowder  6-12% Titanium dioxide  2-6%

The following refers to an example of the double-layer tablet preparedin accordance with the solution of the invention and combining with theanalgesic quick release/sustained release:

A analgesic double-layer controlled-release tablet comprises a quickrelease layer and a sustained-release layer; both quick release layerand sustained-release layer comprise the active ingredients havinganalgesic effect and pharmaceutical excipients, wherein saidsustained-release layer has holes in which the granules of medicine ofthe quick release layer are filled; the diameters of the holes are 2-6mm.

Said active ingredients having analgesic effect refer to one or moreselected from aspirin, magnesium salicylate, sodium salicylate, cholinemagnesium trisalicylate, diflunisal, bisalicylate, ibuprofen,indometacin, flurbiprofen, phenoxy ibuprofen naproxen, nabumetone,piroxicam, phenylbutazone, diclofenac sodium, fenoprofen, ketoprofen,ketorolac, tetraclofenamic acid, sulindac, tolmetin, anisodamine, andthe derivatives of the above-mentioned compounds; said quick releaselayer and said sustained-release layer include the identical ordifferent active ingredients; said pharmaceutical excipients refer toone or more selected from filler, disintegrating agent, lubricant,binder and glidant.

All kinds of pharmaceutical excipients listed below can be selected, butare not limited to the scope of the invention. Actually, all kinds ofpharmaceutical excipients used in the invention can be thepharmaceutical excipients which are used by the technicians in thisfield generally in accordance with actual need, for example, said fillerrefers to one or more selected from lactose monohydrate, lactose,pregelatinized starch and microcrystalline cellulose; saiddisintegrating agent refers to one or more selected from sodiumcarboxymethyl cellulose, croscarmellose sodium, sodium carboxymethylstarch and polyvinylpolypyrrolidone; said lubricant is one or moreselected from stearic acid, magnesium stearate and talcum powder; saidbinder is one or more selected from polyvidone, hydroxypropyl celluloseand hydroxypropyl methylcellulose; and said glidant is silicon dioxide.Moreover, the sustained-release layer in the analgesic double-layertablet also comprises the sustained-release material.

Said sustained-release material is one or more selected fromhydroxypropyl methylcellulose, ethyl cellulose and hydroxypropylcellulose; and said sustained-release layer comprises the followingcomponent by weight:

Analgesic medicine  40-60% Sustained-release material 25~35% Filler13~24% Lubricant 0.5 or 1%   Glidant 0.5 or 1%; 

Said quick release layer and the quick release granule comprise thefollowing component by weight:

Analgesic medicine 30-60%  Disintegrating agent 3~6% Filler 30~60.5%   Binder 0~5% Lubricant 0.5 or 1%     Glidant 0.5 or 1%.   

Said double-layer controlled-release tablet also comprises the coatingwhich includes the following component by weight:

Hydroxypropylmethyl-cellose E5 30% Polysorbate 80 14% Talcum powder  5%Titanium dioxide  2% Water Appropriate

A method of preparing the analgesic double-layer controlled-releaselayer comprises the steps of:

-   1) Preparing the sustained-release granules after mixing the    analgesic medicine, the sustained-release material and the    pharmaceutical excipients; and preparing the quick release granules    after mixing the analgesic medicine and the pharmaceutical    excipients;-   2) Pressing the sustained-release granules into the    sustained-release layer having holes, and putting the    sustained-release layer into a punching die of a tablet press;    implementing the second tableting after filling the quick release    granules to form the double-layer tablet composed of the quick    release layer and the sustained-release layer, wherein the quick    release granules are filled in the holes of the sustained-release    layer.-   3) Implementing coating.

The following refers to one example of the double-layer tablet preparedin accordance with the solution of the invention and combining with thehypnotic quick release/sustained release:

Said hypnotic medicine is one of zolpidem, zaleplon, zopiclone,triazolam, midazolam, flurazepam, diazepam, chlordiazepoxide,nitrazepam, estazolam, alprazolam or lorazepam, and the derivatives ofthe above-mentioned compounds; said sustained-release material is one ormore selected from hydroxypropyl methylcellulose, ethyl cellulose andhydroxy propyl cellulose; and said pharmaceutical excipients is one ormore selected from filler, disintegrating agent, lubricant, binder andglidant.

Said filler is one or more selected from lactose monohydrate, lactose,pregelatinized starch and microcrystalline cellulose; saiddisintegrating agent refers to one or more selected from sodiumcarboxymethyl cellulose, croscarmellose sodium, sodium carboxymethylstarch and polyvinylpolypyrrolidone; said lubricant is one or moreselected from stearic acid, magnesium stearate and talcum powder; saidbinder is one or more selected from polyvidone, hydroxypropyl celluloseand hydroxypropyl methylcellulose; and said glidant is silicon dioxide.

Said sustained-release layer in the double-layer controlled-releasetablet comprises following components by weight:

Hypnotic medicine  8-12% Sustained-release material 30-35% Filler 52-61%Lubricant 0.5 or 1%  Glidant 0.5 or 1%; 

Said quick release layer and the quick release granules comprisefollowing components by weight:

Hypnotic medicine   5~10% Disintegrating agent     2~6% Filler 80.5~91% Binder     0~5% Lubricant 0.5 or 1% Glidant 0.5 or 1%

The method of preparing said hypnotic double-layer controlled-releasetablet comprises steps of

-   1) Preparing the sustained-release granules after mixing the    hypnotic medicine, the sustained-release material and the    pharmaceutical excipients; and preparing the quick release granules    after mixing the hypnotic medicine and the pharmaceutical    excipients;-   2) Pressing the sustained-release granules into the    sustained-release layer having holes, and putting the    sustained-release layer into the punching die of the tablet press;    implementing the second tableting after filling the quick release    granules to form the double-layer tablet composed of the quick    release layer and the sustained-release layer, wherein the quick    release granules are filled in the holes of the sustained-release    layer.-   3) Implementing coating, wherein the formula of the coating layer    and the preparation method are the same as those of the analgesic    double-layer controlled-release tablet.

The invention has the technical effects as follows:

1) Nice Physical Stability

One layer of the double-layer tablet has holes which will be filled bythe components of the other layer during preparation of tablets;therefore, the two layers of tablets are combined together tightly, andcannot be separated easily during storage and transportation.

2) Effectiveness and Safety of the Medicine Improved

It is detected by leaching test that the time limit of disintegration ofthe double-layer controlled-release tablet is 10-30 s; thesustained-release layer shows the zero order release mode, that is,approximately constant release of medicine, which can facilitateimplementation of keeping the stable plasma concentration of themedicine in patient; thus, the effectiveness and the safety of themedicine taken by the patient are improved greatly.

DESCRIPTION OF FIGURES

FIG. 1 is the structure diagram of a double-layer tablet having onehole.

FIG. 2 is the structure diagram of the double-layer tablet having twoholes.

FIG. 3 is the structure diagram of the double-layer tablet having threeholes.

In FIG. 1, FIG. 2 and FIG. 3, 1 indicates the tablet I, 2 indicates thetablet II, and 3 indicates the hole.

FIG. 4 is the leaching curve of the double-layer tablet in hypnoticembodiment 1 (wherein four curves indicate the table I—no holeavailable, table I having holes with diameters 3 mm, tablet I havingholes with diameters 4 mm and table I having holes with diameters 6 mm,respectively)

FIG. 5 indicates comparison of three leaching curves of the double-layertablet having sustained-release layer with holes (diameters 4 mm and 6mm) and the sustained-release layer with no hole available in hypnoticembodiment 1.

FIG. 6 indicates comparison of three leaching curves of the double-layertablet having sustained-release layer with holes (diameters 4 mm and 6mm) and the sustained-release layer with no hole available and onlyquick release layer in hypnotic embodiment 2.

FIG. 7 indicates comparison of three leaching curves of the double-layertablet having sustained-release layer with holes (diameters 4 mm and 6mm) and the sustained-release layer with no hole available in hypnoticembodiment 3.

FIG. 8 indicates comparison of two leaching curves of the double-layertablet having sustained-release layer with holes (diameters 4 mm and 6mm) and the sustained-release layer with no hole available in hypnoticembodiment 4.

FIG. 9 is an in vitro release curve of the double-layercontrolled-release tablet in analgesic embodiment 1.

FIG. 10 is the in vitro release curve of the double-layercontrolled-release tablet in analgesic embodiment 2.

FIG. 11 is the leaching curve of the double-layer controlled-releasetablet in analgesic embodiment 3.

FIG. 12 is the leaching curve of the double-layer controlled-releasetablet in analgesic embodiment 4.

IMPLEMENTATIONS

The double-layer controlled-release tablet in analgesic embodiments 1-5is composed of a quick release layer and a sustained-release layer. SeeTable 1 below for two layers of granules for tabletting the double-layertablets:

TABLE 1 Prescriptions of the double-layer controlled-release tablet inall embodiments (1000 tablets, g) Embodiment Embodiment EmbodimentEmbodiment Embodiment Component 1 2 3 4 5 Sustained-release granulesIbuprofen 250 250 300 200 Ketoprofen Naproxen 300 Hydroxypropyl 50 100 025 150 methylcellulose K1001v Hydroxypropyl 100 50 125 100 25methylcellulose K4M Lactose monohydrate 95 95 65 70 120 Silicon dioxide2.5 2.5 5 2.5 2.5 Magnesium stearate 2.5 2.5 5 2.5 2.5 Total ofsustained-release part 500 500 500 500 500 Sustained-release granulesAcetaminophen 150 Ibuprofen 150 Ketoprofen 75 Naproxen 100 150 Lactose87.5 62.5 50 25 75 Microcrystalline cellulose 63.75 60 40 50 0Polyvidone 8.75 0 0 0 10 Hydroxypropyl cellulose-HF 0 12.5 0 7.5 0Croscarmellose sodium 10 10 7.5 15 12.5 Silicon dioxide 2.5 2.5 1.251.25 1.25 Magnesium stearate 2.5 2.5 1.25 1.25 1.25 Total of quickrelease part 250 250 250 250 250

The coating can be applied to said double-layer tablet and the coatingcomprises following components:

Hydroxypropyl methylcellulose E5 30 Polysorbate 80 14 Talcum powder 5Titanium dioxide 2 80% alcohol/aqueous solution Appropriate

The follows explains the preparation method of the double-layercontrolled-release tablet of analgesic embodiments 1-5.

Analgesic Embodiment 1

1. Preparation of sustained-release granules:

-   (1) Weigh ibuprofen sifted by a 60-mesh screen in accordance with    the formula, hydroxypropyl methylcellulose K100LV, K4M and lactose,    mix them uniformly; then add silicon dioxide and magnesium stearate    which are ½ of the dosages in the formula; and transfer the    materials mixed to a wet type granulator.-   (2) Prepare the ethanol solution with concentration of 70% and    prepare the soft material for the mixture in the first step.-   (3) Implement granulation for the soft material prepared by using a    24-mesh screen.-   (4) Dry and sifting the granules.-   (5) Acquiring the sustained-release granules for preparing the    sustained-release layer.

2. Preparation of quick release granules:

-   (1) Mix ketoprofen, lactose, microcrystalline cellulose, polyvidone    in accordance with the formula and screen the mixture by using the    60-mesh screen; then add silicon dioxide and magnesium stearate,    which are ½ of the dosages in the formula; and mix them uniformly in    a mixer.-   (2) Prepare the ethanol solution with concentration of 80% and    prepare the soft material for the mixture in the first step-   (3) Implement granulation for the soft material prepared by using a    24-mesh screen.-   (4) Dry and sifting the granules.-   (5) Add croscarmellose sodium in accordance with the extra-addition    method and mix croscarmellose sodium and dry granules uniformly.-   (6) Acquiring the quick release granules, which for forming the    quick release layer and filling the holes of the sustained-release    layer.

3. Preparation of double-layer controlled-release tablet:

-   (1) Press the granules of the sustained-release layer, the silicon    dioxide and magnesium stearate left into the sustained-release    tablets with holes in the middle, wherein the diameters are 3 mm, 4    mm and 6 mm, respectively. Moreover, press the sustained-release    tablets without hole.-   (2) Put the sustained-release tablets into a punching die of a    tablet press and fill the granules of quick-release layer; implement    the second compressing in the way of shallow concave punching to    form the double-layer tablets.-   (3) Disperse hydroxypropyl methylcellulose E5 in accordance with the    formula in the ethanol with concentration of 80%; add polysorbate 80    after swelling; stir the mixture until the materials are dissolved    completely and add titanium dioxide and talcum powder; then stir    them uniformly and filter the mixture as the coating liquid.-   (4) Implement coating for the double-layer tablets , increasing the    weight of each tablet for 5%, then dry and solidify the tablets.

The sustained-release layer should be pressed into the sustained-releasetablets without hole, with holes having diameters 3 mm, with holeshaving diameters 4 mm and with holes having diameters 6 mm in thisembodiment to implement the leaching test, in order to investigateeffect of the hole diameter of the sustained-release layer for leaching,wherein the greater the hole diameter of the sustained-release layer is,the faster the leaching speed would be.

The double-layer tablet prepared is applied to leaching test in order toinvestigate the sustained-release effect after quick release, whereinthe quick release layer has been leached completely when sampling anddetecting after 0.5 h, see FIG. 9 for the result. The zero-order releaseeffect is shown in the sustained-release layer, that is, the medicine isapproximately released at constant speed. Moreover, the in vitro releaseat constant speed is useful for keeping the stable plasma concentrationof the patient; and it is worth mentioning that the greater the diameterof the hole of the sustained-release layer, the faster the release speedwould be.

Analgesic Embodiment 2

1. Preparation of sustained-release granules:

-   (1) Weigh ibuprofen sifted by a 60-mesh screen in accordance with    the formula, hydroxypropyl methylcellulose K100LV, K4M and lactose,    mix them uniformly; then add silicon dioxide and magnesium stearate    which are ½ of the dosages in the formula; and transfer the    materials mixed to a wet type granulator.-   (2) Prepare the ethanol solution with concentration of 75% and    prepare the soft material for the mixture in the first step.-   (3) Implement granulation for the soft material prepared by using a    24-mesh screen.-   (4) Dry and sifting the granules.-   (5) Acquiring the sustained-release granules for preparing the    sustained-release layer.

2. Preparation of quick release granules:

-   (1) Mix naproxen, lactose, microcrystalline cellulose and hydroxy    propyl cellulose-HF and sodium carboxymethylcellulose in accordance    with the formula, screen by using the 60-mesh screen; then add    silicon dioxide and magnesium stearate which are ½ of the dosages in    the formula; and mix them uniformly in the mixer.-   (2) Prepare the ethanol solution with concentration of 90% and    prepare the soft material for the mixture in the first step-   (3) Implement granulation for the soft material prepared by using a    24-mesh screen.-   (4) Dry and sifting the granules.-   (5) Acquiring the quick release granules, which for forming the    quick release layer and filling the holes of the sustained-release    layer.

3. Preparation of double-layer controlled-release tablet:

-   (1) Press the granules of the sustained-release layer, the silicon    dioxide and magnesium stearate left into the sustained-release    tablets with holes in the middle, wherein the diameters are 4 mm and    6 mm, respectively.-   (2) Put the sustained-release tablets into a punching die of a    tablet press and fill the granules of quick-release layer; implement    the second compressing in the way of shallow concave punching to    form the double-layer tablets.-   (3) Disperse hydroxypropyl methylcellulose E5 in accordance with the    formula in the ethanol with concentration of 80%; add polysorbate 80    after swelling; stir the mixture until the materials are dissolved    completely and add titanium dioxide and talcum powder; then stir    them uniformly and filter the mixture as the coating liquid.-   (4) Implement coating for the double-layer tablets, increasing the    weight of each tablet for 5%, then dry and solidify the tablets.

Sampling and detection are implemented within 0.25 h in order toinvestigate the disintegrating speed of the quick release layer of thedouble-layer tablet and the sustained-release effect after quick releaseof the double-layer tablet, wherein the quick release layer is leachedmore than 85%; and see FIG. 10 for the result. The zero-order releaseeffect is shown in the sustained-release layer, that is, the medicine isapproximately released at constant speed. Moreover, the in vitro releaseat constant speed is useful for keeping the stable plasma concentrationof the patient; and it is worth mentioning that the greater the diameterof the hole of the sustained-release layer, the faster the release speedwould be.

Analgesic Embodiment 3

1. Preparation of sustained-release granules:

-   (1) Weigh naproxen sifted by a 60-mesh screen in accordance with the    formula, hydroxypropyl methylcellulose K100LV, K4M and lactose, mix    them uniformly; then add silicon dioxide and magnesium stearate    which are ½ of the dosages in the formula; and transfer the    materials mixed to a wet type granulator.-   (2) Prepare the ethanol solution with concentration of 80% and    prepare the soft material for the mixture in the first step.-   (3) Implement granulation for the soft material prepared by using a    24-mesh screen.-   (4) Dry and sifting the granules.-   (5) Acquiring the sustained-release granules for preparing the    sustained-release layer.

2. Preparation of quick release granules:

-   (1) Mix naproxen, lactose, microcrystalline cellulose and hydroxyl    propyl cellulose-HF in accordance with the formula and screen the    sodium carboxymethylcellulose by using the 60-mesh screen; then add    silicon dioxide and magnesium stearate which are ½ of the dosages in    the formula; and mix them uniformly in the mixer.-   (2) Prepare the ethanol solution with concentration of 90% and    prepare the soft material for the mixture in the first step-   (3) Implement granulation for the soft material prepared by using a    24-mesh screen.-   (4) Dry and sifting the granules.-   (5) Acquiring the quick release granules, which for forming the    quick release layer and filling the holes of the sustained-release    layer.

3. Preparation of double-layer controlled-release tablet:

-   (1) Press the granules of the sustained-release layer, the silicon    dioxide and magnesium stearate left into the sustained-release    tablets with holes in the middle, wherein the diameters are 4 mm and    6 mm, respectively. Moreover, press the sustained-release tablets    without hole.-   (2) Put the sustained-release tablets into a punching die of a    tablet press and fill the granules of quick-release layer; implement    the second compressing in the way of shallow concave punching to    form the double-layer tablets.-   (3) Disperse hydroxypropyl methylcellulose E5 in accordance with the    formula in the ethanol with concentration of 80%; add polysorbate 80    after swelling; stir the mixture until the materials are dissolved    completely and add titanium dioxide and talcum powder; then stir    them uniformly and filter the mixture as the coating liquid.-   (4) Implement coating for the double-layer tablets, increasing the    weight of each tablet for 5%, then dry and solidify the tablets.

The leaching tests are implemented for the double-layer tablet preparedin order to investigate the sustained-release effect after quick releaseof the tablet. Seen from the leaching curve, the quick release effectand sustained-release effect are significant; and see the FIG. 11 forthe result.

Analgesic Embodiment 4

1. Preparation of sustained-release granules:

-   (1) Weigh ibuprofen sifted by a 60-mesh screen in accordance with    the formula, hydroxypropyl methylcellulose K100LV, K4M and lactose,    mix them uniformly; then add silicon dioxide and magnesium stearate    which are ½ of the dosages in the formula; and transfer the    materials mixed to a wet type granulator.-   (2) Prepare the ethanol solution with concentration of 70% and    prepare the soft material for the mixture in the first step.-   (3) Implement granulation for the soft material prepared by using a    24-mesh screen.-   (4) Dry and sifting the granules.-   (5) Acquiring the sustained-release granules for preparing the    sustained-release layer.

2. Preparation of quick release granules:

-   (1) Mix ibuprofen, lactose, microcrystalline cellulose and hydroxy    propyl cellulose-HF in accordance with the formula and screen the    sodium carboxymethylcellulose by using the 60-mesh screen; then add    silicon dioxide and magnesium stearate which are ½ of the dosages in    the formula; and mix them uniformly in the mixer-   (2) Prepare the ethanol solution with concentration of 90% and    prepare the soft material for the mixture in the first step-   (3) Implement granulation for the soft material prepared by using a    24-mesh screen.-   (4) Dry and sifting the granules.-   (5) Acquiring the quick release granules, which for forming the    quick release layer and filling the holes of the sustained-release    layer.

3. Preparation of double-layer controlled-release tablet:

-   (1) Press the granules of the sustained-release layer, the silicon    dioxide and magnesium stearate left into the sustained-release    tablets with holes in the middle, wherein the diameters are 4 mm and    6 mm, respectively. Moreover, press the sustained-release tablets    without hole.-   (2) Put the sustained-release tablets into a punching die of a    tablet press and fill the granules of quick-release layer; implement    the second compressing in the way of shallow concave punching to    form the double-layer tablets.-   (3) Disperse hydroxypropyl methylcellulose E5 in accordance with the    formula in the ethanol with concentration of 80%; add polysorbate 80    after swelling; stir the mixture until the materials are dissolved    completely and add titanium dioxide and talcum powder; then stir    them uniformly and filter the mixture as the coating liquid.-   (4) Implement coating for the double-layer tablets to increase the    weight of each tablet for 5%, then dry and solidify the tablets.

The single-layer quick release tablet and the double-layer tablets areprepared to implement the leaching tests in order to investigate thedisintegrating speed of the quick release layer of the medicine and theeffect of the hole diameter of the sustained-release layer to thesustained-release effect, wherein the quick release layer has beenleached more than 90% when sampling and detecting after 0.5 h. Moreover,the linear effect of the in vitro leaching curve of thesustained-release layer having hole diameter of 4 mm is superior to theone of the in vitro leaching curve of the sustained-release layer havinghole diameter of 6 mm in this embodiment; and see FIG. 12 for theresult.

Analgesic Embodiment 5

The preparation method is the same as that in the embodiment 3, but theingredients used are different, seeing the Table 1

The following shall explain the stability test of the analgesicdouble-layer tablet in the invention:

Test 1 Friability Test

The inventor selected 100 double-layer tablets with thesustained-release layers without hole, 100 double-layer tablets with thesustained-release layers having holes with diameters of 3 mm, 4 mm or 6mm respectively to implement the friability testing and comparison studyby using the friability tester, wherein the raw materials, thepharmaceutical excipients and the proportion were implemented inaccordance with the embodiment 1; and see Table 2 for the result.

TABLE 2 Result of friability testing and comparison of double-layertablet Quantity of tablets subjected to Type of the testing breaking in100 tablets double-layer tablet Number Number Number Diameter of tabletsof tablets of holes of hole broken laminated 0 — 20 11 1 6 mm 9 0 1 4 mm1 0 1 3 mm 1 0

It was proved from the result of said friability test that:

-   1) The occurrence rate of breaking of the double-layer tablets    having holes in the invention was reduced greatly, and no lamination    occurred.-   2) The size of the diameter of the hole plays an active role in    preventing lamination; but the degree of breaking of the    double-layer tablet would be affected when the diameter of the hole    is great.

Test 2 Effect of High Humidity to Stability of Medicine

20 double-layer tablets were selected from the embodiment 4respectively, and were placed in the stability testing box to observeafter 24 h, wherein the humidity was set at RH95%; and the temperaturewas set at 25° C. See Table 3 for the result.

TABLE 3 Effect of high humidity to stability of medicine Type of testingNumber of tablets Formula of double-layer tablet subjected to thedouble- Number Diameter lamination among layer tablet of holes of hole100 tablets In accordance 0 — 17 with the 1 6 mm 0 embodiment 4 1 4 mm 01 3 mm 0

The result indicated that the double-layer tablet of the invention stillhad nice stability and was not subjected to lamination under thecondition that the ambient humidity was great, the swelling degree ofthe quick release layer was greater than that of the sustained-releaselayer and the double-layer tablet could not be separated easily althoughthe quick release layer in the prescription included the superdisintegrating agent, and the disintegrating agent had stronghygroscopicity.

Test 3 Effect of Number of Holes in Double-Layer Tablet to Stability

The double-layer tablets with sustained-release layers having no holeand the double-layer tablets having sustained-release layers with one,two and three holes were pressed in accordance with the formula inembodiment 3 (the quick release layer included only the activeingredients and excipient, but did not include the binder); 20 tabletswere selected respectively to implement the friability tests in thefriability tester and carry out comparison study; and see Table 4 forthe result.

TABLE 4 Effect comparison of number of holes to stability Type oftesting Number of tablets subjected double-layer tablet to laminationamong 100 tablets Number of holes Number Number in the sustained- oftablets of tablets Formula release layer broken laminated In accordance0 15 9 with the 1 6 0 embodiment 3 2 2 0 3 1 0

It was proved by said friability test that:

-   1. The occurrence rate of breaking of the double-layer tablets    having holes was reduced greatly, and no lamination occurred.-   2. The number of the tablets broken would be reduced along    increasing number of the holes.

See Table 5 for the prescription of the double-layer controlled-releasetablet in hypnotic embodiments 1-5.

TABLE 5 Component Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4Embodiment 5 Sustained-release granules Zolpidem tartrate 24 24 / / /Zopiclone / / 30 / 36/  Zaleplon / / / 30 Hydroxypropyl 30 60 105 0 90  methylcellulose K1001v Hydroxypropyl 60 30 0 105 15   methylcelluloseK4M Lactose monohydrate 183 183 159 159 156    Silicon dioxide 1.5 1.5 33 1.5 Magnesium stearate 1.5 1.5 3 3 1.5 Total of sustained-release part300 300 300 300 300    Quick release granules Zolpidem tartrate 8 8 / // Zopiclone / / 5 / 10   Zaleplon / / / 5 / Lactose 57 55.5 60 60 55  Microcrystalline cellulose 25.5 25.5 31 25 25.5  Polyvidone 3.5 0 0 03.5 Hydroxypropylmethyl-cellose - 0 5 0 3 0   HF Croscarmellose sodium 44 2 6 5   Silicon dioxide 1 1 1 0.5 0.5 Magnesium stearate 1 1 1 0.5 0.5Total of quick release part 100 100 100 100 100   

The formula of the coating of the double-layer controlled-release tabletin hypnotic embodiments 1-5 is the same as that in said hypnoticembodiment.

The preparation method comprises steps of:

Hypnotic Embodiment 1

1. Preparation of sustained-release granules:

-   {circle around (1)} Weigh zolpidem tartrate,    hydroxypropylmethyl-cellose K100LV, K4M and lactose monohydrate    sifted by the 60-mesh screen in accordance with the formula and mix    them uniformly; then add silicon dioxide and magnesium stearate    which are ½ of the dosages in the formula; and transfer the    materials mixed to the wet type granulator.-   {circle around (2)} Prepare the ethanol solution with concentration    of 70% and prepare the soft material for the mixture in the first    step.-   {circle around (3)} Implement granulation for the soft material    prepared by using a 24-mesh screen.-   {circle around (4)} Dry and sifting the granules.-   {circle around (5)} Acquiring the sustained-release granules for    preparing the sustained-release layer.

2. Preparation of quick release granules:

-   {circle around (1)} Mix zolpidem tartrate, lactose, microcrystalline    cellulose and polyvidone in accordance with the formula and screen    the mixture by using the 60-mesh screen; then add silicon dioxide    and magnesium stearate which are ½ of the dosages in the formula;    and mix them uniformly in the mixer.-   {circle around (2)} Prepare the ethanol solution with concentration    of 80% and prepare the soft material for the mixture in the first    step-   {circle around (3)} Implement granulation for the soft material    prepared by using a 24-mesh screen.-   {circle around (4)} Dry and sifting the granules.-   {circle around (5)} Add croscarmellose sodium and dry granules in    accordance with the extra-addition method and mix them uniformly.-   {circle around (6)} Acquiring the quick release granules which for    forming the quick release layer and filling the holes of the    sustained-release layer.

3. Preparation of double-layer controlled-release tablet:

-   {circle around (1)} Press the granules of the sustained-release    layer, the silicon dioxide and magnesium stearate left into the    sustained-release tablets with holes in the middle, wherein the    diameters are 3 mm, 4 mm and 6 mm, respectively. Moreover, press the    sustained-release tablets without hole.-   {circle around (2)} Put the sustained-release tablets into a    punching die of a tablet press and fill the granules of    quick-release layer; implement the second compressing in the way of    shallow concave punching to form the double-layer tablets.-   {circle around (3)} Disperse hydroxypropylmethyl-cellose E5 in    accordance with the formula in the ethanol with concentration of    80%; add polysorbate 80 after swelling; stir the mixture until the    materials are dissolved completely and add titanium dioxide and    talcum powder; then stir them uniformly and filter the mixture as    the coating liquid.-   {circle around (4)} Implement coating for the double-layer tablets    to increase the weight of each tablet for 5%, then dry and solidify    the tablets.

The sustained-release layer should be pressed into the sustained-releasetablets without hole, with holes having diameters 3 mm, with holeshaving diameters 4 mm and with holes having diameters 6 mm in thisembodiment to implement the leaching test, in order to investigateeffect of the hole diameter of the sustained-release layer to leaching,wherein the greater the hole diameter of the sustained-release layer is,the faster the leaching speed would be. Moreover, see FIG. 4 for theresult.

The double-layer tablet prepared is applied to leaching test in order toinvestigate the sustained-release effect after quick release, whereinthe quick release layer has been leached completely when sampling anddetecting after 0.5 h, see FIG. 5 for the result. See from the figure,the hole of the sustained-released layer can facilitate release atconstant speed.

Hypnotic Embodiment 2

1. Preparation of sustained-release granules:

-   {circle around (1)} Weigh zolpidem tartrate,    hydroxypropylmethyl-cellose K100LV, K4M and lactose monohydrate    sifted by the 60-mesh screen in accordance with the formula and mix    them uniformly; then add silicon dioxide and magnesium stearate    which are ½ of the dosages in the formula; and transfer the    materials mixed to the wet type granulator.-   {circle around (2)} Prepare the ethanol solution with concentration    of 75% and prepare the soft material for the mixture in the first    step-   {circle around (3)} Implement granulation for the soft material    prepared by using a 24-mesh screen.-   {circle around (4)} Dry and sifting the granules.-   {circle around (5)} Acquiring the sustained-release granules for    preparing the sustained-release layer.

2. Preparation of quick release granules:

-   {circle around (1)} Mix zolpidem tartrate, lactose, microcrystalline    cellulose and hydroxy propyl cellulose-HF in accordance with the    formula and screen the sodium carboxymethylcellulose by using the    60-mesh screen; then add silicon dioxide and magnesium stearate    which are ½ of the dosages in the formula; and mix them uniformly in    the mixer.-   {circle around (2)} Prepare the ethanol solution with concentration    of 90% and prepare the soft material for the mixture in the first    step-   {circle around (3)} Implement granulation for the soft material    prepared by using a 24-mesh screen.-   {circle around (4)} Dry and sifting the granules.-   {circle around (5)} Acquiring the quick release granules which for    forming the quick release layer and filling the holes of the    sustained-release layer.

3. Preparation of double-layer controlled-release tablet:

-   {circle around (1)} Press the granules of the sustained-release    layer, the silicon dioxide and magnesium stearate left into the    sustained-release tablets with holes in the middle, wherein the    diameters are 4 mm and 6 mm, respectively. Moreover, press the    sustained-release tablets without hole.-   {circle around (2)} Put the sustained-release tablets into a    punching die of a tablet press and fill the granules of    quick-release layer; implement the second compressing in the way of    shallow concave punching to form the double-layer tablets.-   {circle around (3)} Disperse hydroxypropylmethyl-cellose E5 in    accordance with the formula in the ethanol with concentration of    80%; add polysorbate 80 after swelling; stir the mixture until the    materials are dissolved completely and add titanium dioxide and    talcum powder; then stir them uniformly and filter the mixture as    the coating liquid.-   {circle around (4)} Implement coating for the double-layer tablets    to increase the weight of each tablet for 5%, then dry and solidify    the tablets.

The single-layer quick release tablet and the double-layer tablets areprepared to implement the leaching tests in order to investigate thedisintegrating speed of the quick release layer of the medicine and thesustained-release effect after quick release of the double-layer tablet,wherein the quick release layer has been leached more than 90% whensampling and detecting after 0.25 h. Moreover, see FIG. 6 for theresult.

Hypnotic Embodiment 3

1. Preparation of sustained-release granules:

-   {circle around (1)} Weigh zopiclone, hydroxypropyl methylcellulose    K100LV, K4M and lactose sifted by the 60-mesh screen in accordance    with the formula and mix them uniformly; then add silicon dioxide    and magnesium stearate which are ½ of the dosages in the formula;    and transfer the materials mixed to the wet type granulator.-   {circle around (2)} Prepare the ethanol solution with concentration    of 80% and prepare the soft material for the mixture in the first    step-   {circle around (3)} Implement granulation for the soft material    prepared by using a 24-mesh screen.-   {circle around (4)} Dry and sifting the granules.-   {circle around (5)} (5) Acquiring the sustained-release granules for    preparing the sustained-release layer.

2. Preparation of quick release granules:

-   {circle around (1)} Mix zopiclone, lactose, microcrystalline    cellulose and hydroxy propyl cellulose-HF in accordance with the    formula and screen the sodium carboxymethylcellulose by using the    60-mesh screen; then add silicon dioxide and magnesium stearate    which are ½ of the dosages in the formula; and mix them uniformly in    the mixer.-   {circle around (2)} Prepare the ethanol solution with concentration    of 90% and prepare the soft material for the mixture in the first    step-   {circle around (3)} Implement granulation for the soft material    prepared by using a 24-mesh screen.-   {circle around (4)} Dry and sifting the granules.-   {circle around (5)} Form the quick release layer and fill the holes    of the sustained-release layer after acquiring the

3. Preparation of double-layer controlled-release tablet:

-   {circle around (1)} Press the granules of the sustained-release    layer, the silicon dioxide and magnesium stearate left into the    sustained-release tablets with holes in the middle, wherein the    diameters are 4 mm and 6 mm, respectively. Moreover, press the    sustained-release tablets without hole.-   {circle around (2)} Put the sustained-release tablets into a    punching die of a tablet press and fill the granules of    quick-release layer; implement the second compressing in the way of    shallow concave punching to form the double-layer tablets.-   {circle around (3)} Disperse hydroxypropyl methylcellulose E5 in    accordance with the formula in the ethanol with concentration of    80%; add polysorbate 80 after swelling; stir the mixture until the    materials are dissolved completely and add titanium dioxide and    talcum powder; then stir them uniformly and filter the mixture as    the coating liquid.-   {circle around (4)} Implement coating for the double-layer tablets    to increase the weight of each tablet for 5%, then dry and solidify    the tablets.

The double-layer tablets prepared are applied to leaching test in orderto investigate the sustained-release effect after quick release of thetablet; the quick release layer has been leached completely whensampling and detecting after 0.5 h. Moreover, see FIG. 7 for the result.

Hypnotic Embodiment 4

1. Preparation of sustained-release granules:

-   {circle around (1)} Weigh zaleplon, hydroxypropyl methylcellulose    K100LV, K4M and lactose sifted by the 60-mesh screen in accordance    with the formula and mix them uniformly; then add silicon dioxide    and magnesium stearate which are ½ of the dosages in the formula;    and transfer the materials mixed to the wet type granulator.-   {circle around (2)} Prepare the ethanol solution with concentration    of 80% and prepare the soft material for the mixture in the first    step-   {circle around (3)} Implement granulation for the soft material    prepared by using a 24-mesh screen.-   {circle around (4)} Dry and sifting the granules.-   {circle around (5)} (5) Acquiring the sustained-release granules for    preparing the sustained-release layer.

2. Preparation of quick release granules:

-   {circle around (1)} Mix zaleplon, lactose, microcrystalline    cellulose and hydroxy propyl cellulose-HF in accordance with the    formula and screen the sodium carboxymethylcellulose by using the    60-mesh screen; then add silicon dioxide and magnesium stearate    which are ½ of the dosages in the formula; and mix them uniformly in    the mixer.-   {circle around (2)} Prepare the ethanol solution with concentration    of 90% and prepare the soft material for the mixture in the first    step-   {circle around (3)} Implement granulation for the soft material    prepared by using a 24-mesh screen.-   {circle around (4)} Dry and sifting the granules.-   {circle around (5)} Form the quick release layer and fill the holes    of the sustained-release layer after acquiring the

3. Preparation of double-layer controlled-release tablet:

-   {circle around (1)} Press the granules of the sustained-release    layer, the silicon dioxide and magnesium stearate left into the    sustained-release tablets with holes in the middle, wherein the    diameters are 4 mm and 6 mm, respectively. Moreover, press the    sustained-release tablets without hole.-   {circle around (2)} Put the sustained-release tablets into a    punching die of a tablet press and fill the granules of    quick-release layer; implement the second compressing in the way of    shallow concave punching to form the double-layer tablets.-   {circle around (3)} Disperse hydroxypropyl methylcellulose E5 in    accordance with the formula in the ethanol with concentration of    80%; add polysorbate 80 after swelling; stir the mixture until the    materials are dissolved completely and add titanium dioxide and    talcum powder; then stir them uniformly and filter the mixture as    the coating liquid.-   {circle around (4)} Implement coating for the double-layer tablets    to increase the weight of each tablet for 5%, then dry and solidify    the tablets.

The single-layer quick release tablet and the double-layer tablets areprepared to implement the leaching tests in order to investigate thedisintegrating speed of the quick release layer of the medicine and thesustained-release effect after quick release of the double-layer tablet,wherein the quick release layer has been leached more than 90% whensampling and detecting after 0.25 h. Moreover, see FIG. 8 for theresult.

Hypnotic Embodiment 5

The preparation method is the same as that in the embodiment 3, but theingredients to be used are different, seeing the Table 1

Friability Test and Stability Test of Hypnotic Tablet

100 double-layer tablets having sustained-release layer without hole and100 double-layer tablets having sustained-release layer with holes ofdifferent diameters are prepared respectively in accordance with theformula and the method in the embodiment 1 in order to implementfriability testing and comparison study in the friability testerrespectively; and see Table 6 for the result.

TABLE 6 Testing object Drilling condition Number Number of sustained- oftablets of tablets release layer broken laminated Double-layer tabletWithout hole 12 8 in accordance with Hole with diameter 4 0 the formulain of 6 mm embodiment 1 Hole with diameter 1 0 of 4 mm Hole withdiameter 1 0 of 3 mm

The result indicates that:

1. The double-layer tablets with sustained-release layer having holesare not subjected to lamination.

2. The tablets having small diameters would less likely to be broken.

20 double-layer tablets with sustained-release layer having no hole and20 double-layer tablets with sustained-release layers having holes ofdifferent diameters were prepared in accordance with the formula andmethod in the embodiment 4 respectively, and were placed in thestability testing box, wherein the humidity was set at RH95%; and thetemperature was set at 25° C.

Observe the double-layer tablets after 24 h, and see Table 7 for theresult.

TABLE 7 Testing object Number Drilling condition of of tabletssustained-release layer laminated Double-layer tablets Without hole 17in accordance with Hole with diameter of 6 mm 0 the formula in Hole withdiameter of 4 mm 0 embodiment 4 Hole with diameter of 3 mm 0

The quick release layer of the formula includes the super disintegratingagent having strong hygroscopicity; the degree of swelling of the quickrelease layer is greater than that of the sustained-release layer, andupper layer and the lower layer of the double-layer tablet without holemay be separated from each other when the ambient humidity is great. Thequick release granules in the hole may swell after absorbing themoisture when the sustained-release layer has the hole, and the quickrelease layer may be combined with the sustained-release layer moretightly. Therefore, the double-layer tablet having hole is not subjectedto separation during the test. The result indicated that thedouble-layer tablet of the invention could keep the stability in thehigh-temperature and high-humidity environment.

20 double-layer tablets with sustained-release layer having no hole and20 double-layer tablets with sustained-release layers having differentnumber of holes were prepared in accordance with the formula and methodin the embodiment 3 respectively, and were placed in the friabilitytester to carry out the friability testing and comparison study, whereinthe quick release layer included only the active ingredients and theexcipient, but did not include the binder. Moreover, see Table 8 for theresult.

TABLE 8 Testing object Drilling condition Number Number of sustained- oftablets of tablets release layer broken laminated Double-layer tablets 015 9 in accordance with 1 6 0 the formula in 2 2 0 embodiment 3 3 1 0

The result indicates that:

-   1 The double-layer tablets with sustained-release layer having holes    are not subjected to lamination.-   2. The double-layer tablets having more holes would less likely to    be broken.

Seen from the above-mentioned result, the double-layer tablet preparedin the invention has the physical stability superior to the commondouble-layer tablet, and is more useful for storage and transportation;further, the medicine in the double-layer tablet can be releasedapproximately at constant speed.

1. A kind of double-layer tablet, characterized in that, one layer is ontop of another, wherein the first layer is formed by pressing theingredients of the first layer and comprises one or more holes, thesecond layer is formed by pressing the first layer onto the ingredientsof the second layer and therefore the ingredients of the second layerare filled into the hole(s) of the first layer.
 2. The double-layertablet according to claim 1, wherein the number of said hole is 1-3, andthe diameters of the hole are 1-10 mm.
 3. The double-layer tabletaccording to claim 1, wherein one or both layers include the activeingredients.
 4. The double-layer tablet according to claim 3, whereinthe active ingredients in two layers of the double-layer tablet areidentical or different from each other; and one or more kinds of activeingredients are contained in each layer.
 5. The double-layer tabletaccording to claim 1, wherein each layer of the two-layer refers to therapid-release layer and/or sustained-release layer.
 6. The double-layertablet according to claim 1, wherein the diameter of said hole is 2-6mm.
 7. The double-layer tablet according to claim 1, wherein said holeis penetrating from one side to another side of the first layer.
 8. Thedouble-layer tablet according to claims 1, wherein one layer of thedouble-layer table is rapid-release layer, another layer of thedouble-layer is sustained-release layer; and both the rapid-releaselayer and the sustained-release layer include active ingredients andpharmaceutical excipients.
 9. A kind of painkiller tablet withdouble-layer, characterized in that, one layer is on top of another,wherein the first layer is formed by pressing the ingredients of thefirst layer and comprises one or more holes, the second layer is formedby pressing the first layer onto the ingredients of the second layer andtherefore the ingredients of the second layer are filled into thehole(s) of the first layer, wherein one layer of the painkiller tabletis rapid-release layer, another layer of the painkiller tablet issustained-release layer; and one or both layers comprises the activeingredients, wherein said active ingredients are selected from groupconsist of aspirin, magnesium salicylate, sodium salicylate, cholinemagnesium trisalicylate, diflunisal, bisalicylate, ibuprofen,indomethacin, flurbiprofen, Phenoxy ibuprofen, naproxen, nabumetone,piroxicam, phenylbutazone, diclofenac, fenoprofen, ketoprofen,ketorolac, tetraclofenamic acid, sulindac, tolmetin, anisodamine, andthe derivatives of the above-mentioned compounds.
 10. The painkillertablet according to claim 9, wherein the number of said hole is 1-3 andthe diameters of the hole are 1-10 mm.
 11. The painkiller tabletaccording to claim 9, wherein one or both layers include the activeingredients.
 12. The painkiller tablet according to claim 9, wherein theactive ingredients in two layers of the double-layer tablet areidentical or different from each other; and one or more kinds of activeingredients are contained in each layer.
 13. The painkiller tabletaccording to claim 9, wherein each layer of the two-layer refers to therapid-release layer and/or sustained-release layer.
 14. The painkillertablet according to claim 9, wherein the diameter of the hole is 2-6 mm.15. The painkiller tablet according to claim 9, wherein said hole ispenetrating from one side to another side of the first layer.
 16. Thepainkiller tablet according to claim 9, wherein: the sustained-releaselayer comprises sustained-release material selected from the groupconsisting of: hydroxypropyl methylcellulose, ethyl cellulose,hydroxypropyl cellulose, and any combination thereof.
 17. The painkillertablet according to claim 9, wherein: both layers comprisepharmaceutically acceptable excipients, the pharmaceutically acceptableexcipients are selected from the group consisting of: a filler, adisintegrating agent, a lubricant, a binder, a glidant, and anycombination thereof.
 18. The painkiller tablet according to claim 17,wherein: the filler is selected from the group consisting of: lactosemonohydrate, lactose, pregelatinized starch, microcrystalline cellulose,and any combination thereof; the disintegrating agent is selected fromthe group consisting of: sodium carboxymethyl cellulose, croscarmellosesodium, sodium carboxymethyl starch, polyvinylpolypyrrolidone, and anycombination thereof; the lubricant is selected from the group consistingof: stearic acid, magnesium stearate, talcum powder, and any combinationthereof; the binder is selected from the group consisting of:polyvidone, hydroxy propyl cellulose, hydroxypropyl methylcellulose, andany combination thereof; and the glidant is silicon dioxide.
 19. Thepainkiller tablet according to claim 9, wherein: the sustained-releaselayer comprises the following components in weight percentage: the firstactive ingredient: 40-60%, the sustained-release material: 25-35%, thefiller: 13-24%, the lubricant: 0.5% or 1%, the glidant: 0.5% or 1%; andthe rapid-release layer and rapid-release granules comprise thefollowing components in weight percentage: the second active ingredient:30-60%, the disintegrating agent: 3-6%, the filler: 30-60.5%, thebinder: 0-5%, the lubricant: 0.5% or 1%, and the glidant: 0.5% or 1%.20. The painkiller tablet according to claim 8, further comprisescoating layer with following components in weight percentage, in 80%alcohol in water as a solvent hydroxypropyl methylcellulose E5: 30%,Polysorbate 80: 14%, talcum powder: 5%, and titanium dioxide: 2%.